Cream gels comprising at least one retinoid and benzoyl peroxide

ABSTRACT

Stable cream gel dermatological/cosmetic compositions useful, e.g., for the treatment of acne vulgaris, contain, formulated into a physiologically acceptable medium, a homogeneous dispersion of at least one dispersed retinoid, dispersed benzoyl peroxide, at least one lipophilic compound and at least one gelling agent.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/570,714, filed Dec. 15, 2014, with is a continuation of U.S.application Ser. No. 12/457,788, filed Jun. 22, 2009, now U.S. Pat. No.8,957,112, which is a continuation of PCT/FR2007/052613, filed Dec. 21,2007 and designating the United States (published in the French languageon Jul. 24, 2008 as WO 2008/087354 A2; the title and abstract were alsopublished in English), which claims priority under 35 U.S.C. § 119 ofFrench Patent Application No. FR 0655784, filed Dec. 21, 2006, eachhereby expressly incorporated by reference in its entirety and eachassigned to the assignee hereof.

BACKGROUND OF THE INVENTION Technical Field of the Invention

The present invention relates to dermatological compositions in the formof a cream gel comprising, formulated into a physiologically acceptablemedium, at least one dispersed retinoid and dispersed benzoyl peroxide.

Description of Background and/or Related and/or Prior Art

The use of several categories of active principles is a therapeutic toolto which recourse is frequently had, in particular in the treatment ofdermatological disorders.

Specifically, different anti-fungals, such as allylamine derivatives,triazoles, antibacterials or anti-microbials, such as, for example,antibiotics, quinolones and imidazoles are conventionally combined inthe treatment of dermatological diseases/afflictions. It is also knownto administer peroxides, vitamins D and retinoids in the topicaltreatment of various pathologies related to the skin or mucousmembranes, in particular acne.

The combination of several local treatments (antibiotics, retinoids,peroxides, zinc) is also employed in dermatology to make it possible toenhance the effectiveness of the active principles and to reduce theirtoxicity (Cunliffe W. J., J. Dermatol. Treat., 2000, 11 (suppl.2),S13-S14).

The multiple application of different dermatological products may befairly burdensome and demanding for the patient.

The interest in attempting to obtain a novel treatment which iseffective with regard to dermatological conditions in a stablecomposition which offers a good cosmetic quality, which makes possible asingle application and which makes possible a use which is agreeable tothe patient is thus understood.

Nothing exists among this range of therapies that would encourage oneskilled in the art to combine, in the same composition, benzoyl peroxideand a retinoid.

However, the formulation of such a composition presents severalproblems.

First of all, the effectiveness of the benzoyl peroxide is related toits decomposition when it is brought into contact with the skin. This isbecause it is the oxidizing properties of the free radicals producedduring this decomposition which result in the desired effect.Consequently, in order for the benzoyl peroxide to maintain an optimumeffectiveness, it is important to prevent it from decomposing beforeuse, that is to say during storage.

In point of fact, benzoyl peroxide is an unstable chemical compound,which makes it difficult to formulate it in finished products.

The solubility and the stability of benzoyl peroxide have been studiedby Chellquist et al., in ethanol, propylene glycol and various mixturesof polyethylene glycol 400 (PEG 400) and water (Chellquist E. M. andGorman W. G., Pharm Res., 1992, Vol. 9, 1341-1346).

Benzoyl peroxide is particularly soluble in PEG 400 and ethanol, as isshown in the following table:

Solubility of benzoyl peroxide Solvent (mg/g) PEG 400 39.6 Ethanol 17.9Propylene glycol 2.95 Propylene glycol/water (75:25) 0.36 Glycerol 0.15Water 0.000155

This document furthermore specifies that the stability of benzoylperoxide is strongly influenced by the chemical composition of theformulation and by the storage temperature. Benzoyl peroxide is highlyreactive and decomposes in solution at low temperature due to theinstability of its peroxide bond.

The authors thus find that benzoyl peroxide in solution decomposes moreor less rapidly in all the solvents studied according to the type ofsolvent and its concentration.

The decomposition times of benzoyl peroxide in PEG 400 (0.5 mg/g), inethanol and in propylene glycol are 1.4, 29 and 53 days respectively at40° C.

Such a decomposition does not make possible the formulation of a productuseful for sale.

Furthermore, it is known that benzoyl peroxide is more stable in waterand propylene glycol when it is in suspension (i.e., in the dispersedform), since it is not decomposed after storing for 90 days in thesesolvents.

Thus, to limit the problem of rapid instability of benzoyl peroxide insolution, it has proven to be advantageous to formulate benzoyl peroxidein the dispersed form. However, this type of formulation is notcompletely satisfactory insofar as the benzoyl peroxide is still foundto be decomposed in the finished product.

Another difficulty to be overcome in the preparation of a compositioncomprising both benzoyl peroxide and a retinoid is that the majority ofretinoids are particularly sensitive to natural oxidation, to visiblelight and ultraviolet radiation and, as benzoyl peroxide is a strongoxidizing agent, the chemical compatibility of these compounds in oneand the same formulation presents numerous problems of stability fromthe physical and chemical viewpoint.

A stability study was carried out on two retinoids by combining twocommercial products, one comprising a retinoid (tretinoin or adapalene)and the second based on benzoyl peroxide (B. Martin et al., Br. J.Dermatol., (1998) 139, (suppl. 52), 8-11).

The presence of the formulation based on benzoyl peroxide causes veryrapid decomposition of the oxidation-sensitive retinoids: 50% of thetretinoin is measured as decomposing in 2 hours and 95% in 4 hours. Inthe composition in which the retinoid is adapalene, no decomposition ofthe adapalene was measured during 24 hours. This study confirms thatbenzoyl peroxide is decomposed and decomposes oxidation-sensitiveretinoids over time by gradually releasing benzoic acid in finishedproducts.

In point of fact, it is clear that the decomposition of benzoyl peroxideand retinoids is not desirable insofar as it is harmful to theeffectiveness of the composition in which they are present.

Nothing would suggest combining of these two active agents to obtain astable composition of emulsion type, it being known that it wasconventionally recognized that the presence of benzoyl peroxidechemically and physically destabilized this type of composition.

The formulation as a cream gel of benzoyl peroxide and a retinoid can beadvantageous for topical treatments, such as that of acne, as, whilecontributing emollience, it avoids in particular leaving an excessivelygreasy feel remaining on the skin.

In point of fact, another difficulty to be overcome in the preparationof such a composition comprising in particular dispersed activeprinciples, such as adapalene and benzoyl peroxide, is the sedimentationof the active principles. This is because, while the “light” feel ofsuch a formulation is related to the fact that the external phase isaqueous, it also depends on its composition and in particular on thepresence of thickeners. In point of fact, in cream gels, the thickenersfor the fatty phase, such as waxes and solid fatty alcohols and esters,are greatly reduced, to the advantage of gelling agents for the aqueousphase. However, the majority of gelling agents for the aqueous phase aredestabilized by the benzoic acid which is released during thedecomposition of the benzoyl peroxide.

Specifically, the thickening agents most commonly used for theformulation of gels with benzoyl peroxide are acrylic acid polymers(Carbomer) and celluloses, alone or in combination with silicates.

In point of fact, the use of carbomers in compositions of aqueous geltype does not give good results in terms of chemical stability of thebenzoyl peroxide and in terms of rheological stability. As described byBollinger (Bollinger, Journal of Pharmaceutical Science, 1977, Vol. 5),a loss of 5% to 20% of benzoyl peroxide after 2 months at 40° C.,depending on the neutralizing agent of the carbomer used, was observed.Furthermore, the release of benzoic acid brings about depolymerizationof the carbomers, giving a fall in viscosity which may bring about phaseseparation.

In other gels composed of a mixture of hydroxypropylcellulose and ofmagnesium aluminum silicate, a drop in viscosity over time is alsoobserved and results in sedimentation of the suspended active principlesand in the dispersion in the finished product being heterogeneous.

This instability of benzoyl peroxide gels is harmful to theireffectiveness and to their cosmetic quality and it is highly probablethat it is reencountered in cream gels. A finished product, inparticular when it concerns pharmaceutical or cosmetic compositions,must maintain, throughout its lifetime, precise physicochemical criteriawhich make it possible to guarantee its pharmaceutical or cosmeticquality respectively. Among these criteria, it is necessary for therheological properties to be retained. They define the behavior and thetexture of the composition during application but also the properties ofrelease of the active principle [SFSTP Commission report 1998] and thehomogeneity of the product when the active principles are presenttherein in the dispersed state.

The need thus exists to have available a physically and chemicallystable cream gel comprising benzoyl peroxide and a retinoid.

SUMMARY OF THE INVENTION

Dermatological compositions have now been developed which meet thisneed. Such compositions are cream gels which comprise:

dispersed benzoyl peroxide, in particular in the free or encapsulatedform,

at least one retinoid,

at least one lipophilic compound constituting the fatty phase, and

at least one pH-independent gelling agent which has good physicalstability, that is to say which does not exhibit a drop in viscosityover time and at temperatures of from 4° C. to 40° C., and whichmaintains good chemical stability for the two active principles (benzoylperoxide and retinoid), that is to say that decomposition of activeprinciples over time and at temperatures from 4° C. to 40° C. is notobserved.

The compositions of the present invention can be provided in all theformulation forms normally employed for topical application and inparticular in the form of a cream gel with a semiliquid consistency ofthe milk type or with a solid consistency of the cream type obtained bydispersion of a fatty phase in an aqueous phase (O/W).

One skilled in this art will take care to select the excipientsconstituting the compositions according to the invention as a functionof the consistency desired and so that the advantageous properties ofthe composition are maintained.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

The compositions according to the invention can in particular comprise,in addition to at least one retinoid, benzoyl peroxide, a fatty phaseand at least one pH-independent gelling agent, one or more of thefollowing ingredients:

a) one or more wetting agents,

b) one or more chelating agents,

c) an aqueous phase,

d) one or more additives.

It has now surprisingly been determined that it is possible to obtain aperfect dispersion of active principles by following a specificpreparation process. This preparation process makes it possible toobtain an optimum particle size and a homogeneous dispersion of the twoactive principles in the composition while guaranteeing the physicalstability of the product.

The present invention thus features dermatological compositions in theform of cream gels comprising, formulated into a physiologicallyacceptable medium, at least one dispersed retinoid and dispersed benzoylperoxide.

The compositions according to the invention are preferably in the formof an aqueous cream gel.

The cream gel is characterized by the presence of gelling agents for theaqueous phase and of a fatty phase. On the other hand, there is (are) noemulsifier(s) which differentiates cream gels from emulsions.

The term “emulsifiers” means amphiphilic compounds which have ahydrophobic part having an affinity for the oil and a hydrophilic parthaving an affinity for the water, thus creating a connection from thetwo phases. Ionic or nonionic emulsifiers thus stabilize O/W emulsionsby being adsorbed at the interface and by forming lamellar layers ofliquid crystals.

In particular, the compositions according to the invention arephysically and chemically stable.

The term “physiologically acceptable medium” means a medium compatiblewith topical application on the skin, superficial body growths and/ormucous membranes.

The compositions according to the invention comprise at least oneretinoid. The term “retinoid” means any compound which binds to RARand/or RXR receptors.

Exemplary are, as retinoid, retinoic acid, tretinoin, tazarotene andthose described in the following:

U.S. Pat. Nos. 4,666,941, 4,581,380, EP 0210929, EP 0232199, EP 0260162,EP 0292348, EP 0325540, EP 0359621, EP 0409728, EP 0409740, EP 0552282,EP 0584191, EP 0514264, EP 0514269, EP 0661260, EP 0661258, EP 0658553,EP 0679628, EP 0679631, EP 0679630, EP 0708100, EP 0709382, EP 0722928,EP 0728739, EP 0732328, EP 0749937, EP 0776885, EP 0776881, EP 0823903,EP 0832057, EP 0832081, EP 0816352, EP 0826657, EP 0874626, EP 0934295,EP 0915823, EP 0882033, EP 0850909, EP 0879814, EP 0952974, EP 0905118,EP 0947496, WO98/56783, WO99/10322, WO99/50239 and WO99/65872.

Due to their ability to bind RAR and/or RXR receptors, the compoundsresulting from the family of the benzonaphthalene retinoids, such asdescribed in EP 0199636, are also included in the invention.

Preferably, the naphthoic acid derivatives will be selected and inparticular:

-   6-(3-methylphenyl)-2-naphthoic acid and its methyl ester,-   6-(4-(tert-butyl)phenyl)-2-naphthoic acid and its methyl ester,-   6-(3-(tert-butyl)phenyl)-2-naphthoic acid and its methyl ester,-   6-(3,4-dimethoxyphenyl)-2-naphthoic acid and its methyl ester,-   6-(p-(1-adamantylthio)phenyl)-2-naphthoic acid and its methyl ester,-   6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid (adapalene) and    its methyl ester,-   the methyl ester of    6-[3-(1-adamantyl)-4-(tert-butyldimethylsilyloxy)phenyl]-2-naphthoic    acid,-   the methyl ester of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic    acid,-   6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid,-   the methyl ester of 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic    acid,-   6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid,-   the methyl ester of 6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic    acid,-   6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid,-   the methyl ester of    6-[3-(1-adamantyl)-4-methoxyphenyl]-4-acetoxy-1-methyl-2-naphthoic    acid,-   6-[3-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy-1-methyl-2-naphthoic    acid,-   the methyl ester of    6-[3-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy-1-methyl-2-naphthoic    acid,-   the methyl ester of    6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid,-   6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid,-   6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalenemethanol,-   the ethyl amide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic    acid,-   the morpholide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic    acid,-   the methyl ester of 6-[3-(tert-butyl)-4-methoxyphenyl]-2-naphthoic    acid,-   6-[3-(tert-butyl)-4-methoxyphenyl]-2-naphthoic acid,-   the methyl ester of    6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid,-   6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid.

In particular, preference will be given to adapalene and its salts.

The term “salts of adapalene” means the salts formed with apharmaceutically acceptable base, in particular inorganic bases, such assodium hydroxide, potassium hydroxide and ammonia, or organic bases,such as lysine, arginine or N-methylglucamine.

The term “salts of adapalene” also means the salts formed with fattyamines, such as dioctylamine and stearylamine.

Of course, the amount of the two active agents, benzoyl peroxide andretinoid, in the compositions according to the invention will depend onthe combination selected and thus particularly on the retinoid underconsideration and on the quality of the treatment desired.

The preferred retinoid concentrations are from 0.0001 to 20% by weight,with respect to the total weight of the composition.

Preferably, in the case of adapalene, the compositions according to theinvention comprise from 0.001% to 5% by weight and advantageously from0.01% to 1% by weight of adapalene, with respect to the total weight ofthe composition, preferentially from 0.01% to 0.5% by weight, preferablyfrom 0.1% to 0.4% by weight of adapalene, more preferably still 0.3% byweight of adapalene.

The benzoyl peroxide can just as easily be employed in the free form orelse in an encapsulated form, for example in a form adsorbed on orabsorbed in any porous support. It can, for example, be benzoyl peroxideencapsulated in a polymeric system composed of porous microspheres, suchas, for example, microsponges marketed under the trademark ofMicrosponges P009A Benzoyl Peroxide by Amcol.

To provide an order of magnitude, the compositions according to theinvention advantageously comprise from 0.0001% to 20% by weight ofbenzoyl peroxide and from 0.0001% to 20% by weight of retinoid, withrespect to the total weight of the composition, and preferably from0.025% to 10% by weight of benzoyl peroxide and from 0.001% to 10% byweight of retinoid respectively, with respect to the total weight of thecomposition.

For example, in the compositions for the treatment of acne, the benzoylperoxide is preferably included at concentrations ranging from 2% to 10%by weight and more particularly from 2.5% to 5% by weight, with respectto the total weight of the composition. The retinoid for its part isincluded in this type of composition at concentrations generally rangingfrom 0.01% to 1% by weight, with respect to the total weight of thecomposition.

Advantageously, the particle size of the retinoid and of the benzoylperoxide is such that at least 80% by number of the particles andpreferably at least 90% by number of the particles have a diameter ofless than 25 μm and at least 99% by number of the particles have adiameter of less than 100 μm.

Preferably, the cream gel according to the invention comprises one ormore gelling agents and/or suspending agents and/or pH-independentgelling agents.

The term “pH-independent gelling agent” means a gelling agent capable ofconferring a viscosity on the composition sufficient to keep theretinoid and the benzoyl peroxide in suspension, even under theinfluence of a variation in pH due to the release of benzoic acid by thebenzoyl peroxide.

Exemplary are, as non-limiting examples of gelling agents and/orsuspending agents and/or pH-independent gelling agents which canparticipate in the compositions according to the invention, of theacrylates/C₁₀₋₃₀ alkyl acrylate crosspolymer marketed under thetrademark of Pemulen TR-1 or Pemulen TR-2 by Noveon,“electrolyte-insensitive” carbomers, marketed under the trademark ofUltrez 20®, Carbopol 1382 or Carbopol ETD2020NF® by Noveon,polysaccharides, with, as non-limiting examples, xanthan gum, such asthe Xantural 180®, marketed by Kelco, guar gum, chitosans, carrageenans,in particular divided into four main families: κ, λ, β and ω, such asthe Viscarin® products and Gelcarin® products marketed by IMCD,cellulose and its derivatives, such as hydroxypropylmethylcellulose, inparticular the product marketed under the trademark of Methocel E4Premium by Dow Chemical, or hydroxyethylcellulose, in particular theproduct marketed under the trademark of Natrosol HHX 250° by Aqualon, oralso the product “microcrystalline cellulose and carboxymethyl cellulosesodium” marketed under the trademark of Avicel CL-611 by FMC Biopolymer,the family of magnesium aluminum silicates, such as Veegum K, marketedby Vanderbilt, the family of acrylic polymers coupled to hydrophobicchains, such as the PEG-150/decyl/SMDI copolymer marketed under thetrademark of Aculyn 44 (polycondensate comprising at least, ascomponents, a polyethylene glycol comprising 150 or 180 mol of ethyleneoxide, decyl alcohol and methylenebis(4-cyclohexyl isocyanate) (SMDI),at 35% by weight in a mixture of propylene glycol (39%) and water(26%)), the family of modified starches, such as the modified potatostarch marketed under the trademark of Structure Solanace, and alsotheir mixtures, and gelling agents of the family of polyacrylamides,such as the sodium acryloyldimethyltauratecopolymer/isohexadecane/polysorbate 80 mixture marketed under thetrademark Simulgel 600PHA by Seppic or the polyacrylamide/C13-14isoparaffin/laureth-7 mixture, such as, for example, that marketed underthe trademark of Sepigel 305 by Seppic.

The preferred gelling agents result from the family of polyacrylamides,such as Simulgel 600PHA or Sepigel 305; “electrolyte-insensitive”carbomers, such as Carbopol ETD2020 NF; polysaccharides, such as xanthangum; cellulose derivatives, such as hydroxypropylmethylcellulose orhydroxyethylcellulose; or magnesium aluminum silicates, alone or as amixture.

The gelling agent or suspending agent as described above can be employedat the preferred concentrations ranging from 0.001% to 15% to morepreferably ranging from 0.1% to 5%.

Exemplary are, among chelating agents, ethylenediaminetetraacetic acid(EDTA), diethylenetriaminepentaacetic acid (DTPA),ethylenediaminedi(o-hydroxyphenylacetic acid) (EDDHA),(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA),ethylenediaminedi(o-hydroxy-p-methylphenylacetic acid) (EDDHMA) andethylenediaminedi(5-carboxy-2-hydroxyphenylacetic acid) (EDDCHA).

A preferred chelating agent is ethylenediaminetetraacetic acid (EDTA).

The concentrations of chelating agent can vary from 0% to 1.5% byweight, preferably from 0.05% to 0.5% by weight, with respect to thetotal weight of the composition.

The compositions of the invention can comprise one or more wettingagents at concentrations of 0% to 20% by weight, preferably of 0% to 10%by weight, with respect to the total weight of the composition. Whenthese ingredients are present in the composition, they are atconcentrations ranging from 0.001% to 20% by weight, preferentially from0.1% to 10% by weight, preferably from 0.1% to 7% by weight and morepreferably still from 2% to 7% by weight, with respect to the totalweight of the composition. They should not dissolve the activeprinciples at the percentage used, should not cause exothermic reactionsharmful to the benzoyl peroxide, should help in dispersing the activeprinciples well and should have anti-foaming properties. The wettingpower is the tendency of a liquid to spread out over a surface.

Preferably, the wetting agents are ones which can exhibit an HLB(Hydrophilic-Lipophilic Balance) of 7 to 16. Exemplary are thePoloxamers and more particularly Synperonic PE/L44 and/or SynperonicPE/L62, marketed by Uniqema, glycols, such as propylene glycol,dipropylene glycol, propylene glycol dipelargonate, lauroglycol orethoxydiglycol, sorbitan esters, such as POE (20) sorbitan monooleate,marketed under the trademark of Tween 80 by Uniqema, and POE (20)sorbitan monostearate, marketed under the trademark of “Tween 60” byUniqema, ethers of fatty alcohols, such as Ceteareth-20, marketed underthe trademark of Eumulgin B2 by Cognis, glycerol esters, such asglycerol monostearate, marketed under the trademark of “Cutina GMS” byCognis, polyoxyethylene (21) stearyl ether, marketed under the trademarkof Brij 721 by Uniqema, methyl glucose sesquistearate, marketed underthe trademark of Glucate SS by Noveon, or PEG-20 methyl glucosesesquistearate, marketed under the trademark of Glucamate SSE-20 byNoveon.

Preferred wetting agents, which can preferably exhibit an HLB of 10 to14, are compounds of the family of the Poloxamers and more particularlySynperonic PE/L44 and/or Synperonic PE/L62 or of glycols, such aspropylene glycol, dipropylene glycol, propylene glycol dipelargonate,lauroglycol or ethoxydiglycol.

The particularly preferred wetting agents are propylene glycol orSynperonic PE/L44 (polyethylene-polypropylene glycol;polyoxyethylene-polyoxypropylene block copolymer).

According to the invention, the cream gel comprising the benzoylperoxide and a retinoid advantageously comprises at least water and atleast one gelling agent and/or suspending agent and/or pH-independentgelling agent and can also comprise one or more wetting agents.

The compositions according to the invention also comprise a fatty phase.This fatty phase can comprise lipophilic compounds, alone or as amixture, such as, for example, vegetable, mineral, animal or syntheticoils, silicone oils and mixtures thereof.

Exemplary mineral oils are liquid paraffins with different viscosities,such as Primol 352®, Marcol 82® or Marcol 152°, marketed by Esso.

Exemplary vegetable oils are sweet almond oil, palm oil, soybean oil,sesame oil or sunflower oil.

Exemplary animal oils are lanolin, squalene, fish oil or mink oil, with,as derivative, the squalane marketed under the trademark Cosbiol® byLaserson.

Exemplary synthetic oils are an ester, such as cetearyl isononanoate,for example the product marketed under the trademark of Cetiol SN PH® byCognis France, isopropyl palmitate, for example the product marketedunder the trademark of Crodamol IPP® by Croda, diisopropyl adipate,marketed under the trademark of Crodamol DA by Croda, or caprylic/caprictriglyceride, such as Miglyol 812®, marketed by Hüls/Univar.

Exemplary volatile or non-volatile silicone oils are dimethicones, suchas the products marketed under the trademark of Q7-9120 Silicone Fluidwith a viscosity of from 20 cSt and 12 500 cSt or the product marketedunder the trademark ST-Cyclomethicone-5 NF® by Dow Corning.

Solid fatty substances can also be included, such as natural orsynthetic waxes. In this case, one skilled in this art will adjust theheating temperature of the preparation according to the presence orabsence of these solids.

For the compositions according to the invention, synthetic oils andsilicone oils and more particularly Marcol 152® and ST-Cyclomethicone 5NF® are preferred.

The aqueous phase of the cream gels according to the invention cancomprise water. This water can in particular be a floral water, such ascornflower water, or a natural thermal or mineral water, for exampleselected from among water from Vittel, waters from the Vichy basin,water from Uriage, water from La Roche-Posay, water from Avène or waterfrom Aix-les-Bains.

The said aqueous phase can be present at a content of from 10% to 90% byweight, with respect to the total weight of the composition, preferablyfrom 20% to 80% by weight.

The compositions can additionally comprise any additive conventionallyused in the cosmetics or pharmaceutical field, such as a stabilizingagent for benzoyl peroxide (by way of example, sodium docusate or sodiumC₁₄₋₁₆ olefinsulphonate), neutralizing agents of normal inorganic ororganic base or acid type (by way of example, triethanolamine, 10%sodium hydroxide solution, the citric acid/sodium citrate buffer or thesuccinic acid/sodium succinate buffer), antioxidants, sunscreens,preservatives, fillers, electrolytes, humectants and/or emollients,colorants, fragrances, essential oils, cosmetic active principles,moisturizing agents, vitamins, essential fatty acids, sphingolipids,self-tanning compounds, such as DHA, soothing agents and protectiveagents for the skin, such as allantoin. Of course, one skilled in thisart will take care to select this or these optional additional compoundsand/or their amounts in such a way that the advantageous properties ofthe compositions according to the invention are not, or notsubstantially, detrimentally affected.

These additives can be present in the composition in a proportion of0.001% to 20% by weight, with respect to the total weight of thecomposition.

Exemplary preservatives are benzalkonium chloride, bronopol,chlorhexidine, chlorocresol and its derivatives, ethyl alcohol,phenethyl alcohol, phenoxyethanol, potassium sorbate, diazolidinylurea,benzyl alcohol, parabens or their mixtures.

Exemplary humectants and/or emollients are glycerol and sorbitol, sugars(by way of example, glucose or lactose), PEGs (by way of example, LutrolE400), urea or amino acids (by way of example, serine, citrulline oralanine).

In particular, the present invention also features pharmaceutical orcosmetic compositions in the form of a cream gel comprising, formulatedinto a physiologically acceptable medium compatible with topicalapplication to the skin, superficial body growths or mucous membranes,the ingredients (expressed as percentage by weight) selected from among:

from 0.001% to 5%, preferably from 0.01% to 0.5%, of a retinoid andpreferably of a naphthoic acid derivative;

from 0.025% to 10%, preferably from 2% to 10%, of benzoyl peroxide;

from 30% to 95%, preferably from 50% to 85%, of water;

from 0.01% to 15%, preferably from 0.1% to 5%, of one or more gellingagents and/or suspending agents and/or pH-independent gelling agents;

from 2% to 50%, preferably from 5% to 30%, of fatty phase;

from 0% to 1.5%, preferably from 0.05% to 0.5%, of chelating agents;

from 0% to 10%, preferably from 2% to 7%, of one or more wetting agents;

from 0% to 3%, preferably from 0.05% to 1%, of preservatives;

from 0% to 20%, preferably from 2% to 15%, of humectants and/oremollients;

from 0% to 3%, preferably from 0.05% to 2%, of stabilizing agents;

from 0% to 10%, preferably from 0.1% to 5%, of neutralizing agents.

The present invention also features administration of the compositionsas described above as medicaments.

The invention also features the use of the novel compositions asdescribed above in cosmetics and in dermatology.

Due to the keratolytic, bactericidal and anti-inflammatory activity ofbenzoyl peroxide and the marked activity of retinoids in the fields ofcell differentiation and proliferation, the compositions of theinvention are particularly well suited for the following therapeuticfields:

1) for treating dermatological conditions linked to a disorder ofkeratinization involving differentiation and proliferation, inparticular for treating acne vulgaris, comedonic or polymorphic acne,acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondaryacnes, such as solar, drug or occupational acne, or hidradenitissuppurativa,

2) for treating other types of disorders of keratinization, inparticular ichthyoses, ichthyosiform conditions, Darier's disease,palmoplantar keratoderma, leucoplakia and leucoplakiform conditions, orcutaneous or mucosal (oral) lichen,

3) for treating other dermatological conditions linked to a disorder ofkeratinization with an inflammatory and/or immunoallergic component and,in particular, all forms of psoriasis, whether cutaneous, mucosal orungual, and even psoriatic rheumatism, or alternatively cutaneous atopy,such as eczema, or respiratory atopy or alternatively gingivalhypertrophy; the compounds can also be used in some inflammatoryconditions not exhibiting disorder of keratinization, such asfolliculitis,

4) for treating all dermal or epidermal proliferations, whether they arebenign or malignant and whether they are or are not of viral origin,such as common warts, flat warts, molluscum contagiosum andepidermodysplasia verruciformis, florid or oral papillomatoses, and theproliferations which can be induced by ultraviolet radiation, inparticular in the case of actinic keratoses,

5) for repairing or combating skin aging, whether photoinduced orchronologic, or for reducing pigmentations, or any pathology associatedwith chronologic or actinic aging;

6) for preventively or curatively treating disorders of cicatrization orskin ulcers, for preventing or repairing stretch marks, or alternativelyfor promoting cicatrization,

7) for combating disorders of the sebaceous function, such ashyperseborrhoea of acne or simple seborrhoea,

8) in the treatment of any condition of fungal origin on the skin, suchas tinea pedis and tinea versicolor,

9) in the treatment of dermatological conditions with an immunologicalcomponent,

10) in the treatment of skin disorders due to exposure to UV radiation,and

11) in the treatment of dermatological conditions linked to inflammationor infection of the tissues surrounding the hair follicle, in particulardue to microbial colonization or infection, in particular impetigo,seborrhoeic dermatitis, folliculitis or sycosis barbae, or involving anyother bacterial or fungal agent.

The compositions according to the invention are particularly useful forthe preventive or curative treatment of acne vulgaris.

This invention also features pharmaceutical compositions intended forthe prevention and/or treatment of dermatological conditions linked todisorders of cell differentiation and/or proliferation and/or ofkeratinization, preferably acne vulgaris.

The compositions according to the invention are also useful in body andhair hygiene.

The present invention thus also features the cosmetic administration ofa composition according to the invention for the treatment of skin witha tendency towards acne, for causing hair growth or preventing hairloss, for combating the greasy appearance of the skin or hair, inprotecting against the harmful effects of the sun or for preventingand/or combating photoinduced or chronologic aging.

Preferably, the said compositions according to the invention areadministered topically.

The present invention also features a process for the preparation of acomposition as described above. Such a process is characterized in thatit comprises a stage of mixing a physiologically acceptable medium withat least one naphthoic acid derivative and at least benzoyl peroxide.

The other optional excipients and additives will be introduced accordingto the chemical nature of the compounds and the formulation formselected.

Generally, the preparation of a composition according to the inventionis carried out according to the following main process:

a) mixing at least one retinoid with water until it has completelydispersed, to obtain active phase 1;

b) mixing the benzoyl peroxide with water until it has completelydispersed, to obtain active phase 2;

c) mixing at least one gelling agent and/or suspending agent and/orpH-independent gelling agent with water, optionally one or morechelating agents, one or more preservatives, one or more humectantsand/or emollients, one or more stabilizing agents and the hydrophilicadditives, to obtain the aqueous phase;

d) optionally, mixing at least two lipophilic compounds, to obtain thefatty phase;

e) mixing the 2 active phases obtained in a) and b), to obtain a singleactive phase;

f) introducing the single active phase obtained in e) into the aqueousphase obtained in c);

g) introducing the single compound of the fatty phase or optionally thefatty phase obtained in d), to obtain a cream gel;

h) if necessary, the heat-sensitive additives are added;

i) if necessary, a neutralizing agent for the gelling agent isintroduced into the cream gel obtained in g) or h);

j) if necessary, further water is added.

Generally, the formulation of a composition according to the inventiontakes place thus according to the following alternative process:

a′) Stages a) and b) are combined, so as to obtain stage a′), whichcorresponds to the mixing of at least one retinoid and benzoyl peroxidewith water and at least one wetting agent until they have completelydispersed, to obtain the single active phase.

Stages c), d), f), g), h), i) and j) of the main process remainunchanged. As regards step e), this is deleted.

According to a specific embodiment, the preparation of a compositionaccording to the invention takes place, by way of example, according tothe following main process:

a) the retinoid, preferably the naphthoic acid derivative, is mixed withat least one wetting agent in water until the said naphthoic acidderivative has completely dispersed, to obtain active phase 1;

b) the benzoyl peroxide is mixed with at least one wetting agent inwater until it has completely dispersed, to obtain active phase 2;

c) one or more gelling agents and/or suspending agents and/orpH-independent gelling agents (with the exception of the polyacrylamide)and optionally one or more chelating agents, one or more preservatives,one or more humectants and/or emollients, one or more stabilizing agentsand the heat-insensitive hydrophilic additives are dissolved in thewater with stirring, if necessary under hot conditions. Stirring ismaintained and optional heating is maintained until homogeneity isachieved, to obtain the aqueous phase;

d) optionally, at least oils, and optionally solid fatty substances, andpreservatives and the heat-insensitive lipophilic additives are mixed,if necessary under hot conditions, until homogeneity is achieved, toobtain the fatty phase;

e) active phases 1 and 2 are mixed, so as to obtain a single activephase;

f) the single active phase obtained in e) is added to the aqueous phaseobtained in c);

g) optionally, the polyacrylamide is introduced into the phase obtainedin f),

h) the single fatty phase constituent or optionally the said fatty phaseobtained in d) is introduced into the phase obtained in f) or g), toobtain a cream gel;

i) if necessary, the heat-sensitive additives are added;

j) if necessary, a neutralizing agent for the gelling agent isintroduced into the cream gel obtained in h) or i), to obtain thedesired pH;

k) if necessary, further water is added.

In particular, the formulation of a composition according to theinvention takes place thus according to the following alternativeprocess:

a′) Stages a) and b) are combined, so as to obtain stage a′), whichcorresponds to the mixing of at least one retinoid and benzoyl peroxidewith water and at least one wetting agent until they have completelydispersed, to obtain the single active phase.

Stages c), d), f), g), h), i), j) and k) of the main process remainunchanged. As regards stage e), it is deleted.

More specifically, by way of example, the main process for thepreparation of the compositions according to the invention comprises thefollowing stages:

Stage a: Preparation of Active Phase 1:

The active principle (adapalene), a portion of the purified water andthe wetting agent or agents (propylene glycol, Synperonic PE/L62,Synperonic PE/L44 type) are weighed in a beaker. They are dispersed withstirring until they have completely dispersed.

Stage b: Preparation of Active Phase 2:

The active principle (benzoyl peroxide), a portion of the purified waterand the wetting agent or agents (propylene glycol, Synperonic PE/L62,Synperonic PE/L44 type) are weighed in a beaker. They are dispersed withstirring until they have completely dispersed.

Stage c: Preparation of the Aqueous Phase:

The remaining purified water, the gelling agent or agents (Carbopol,Pemulen TR1, Xantural, Methocel type) and/or suspending agent or agents(Avicel CL-611 type) and/or pH-independent gelling agent or agents (withthe exception of Simulgel 600PHA) and optionally one or more chelatingagents (EDTA type), one or more humectants and/or emollients (glyceroltype), one or more stabilizing agents (sodium docusate type), one ormore preservatives (methylparaben type) and the heat-insensitivehydrophilic additives are introduced with stirring into a beaker, ifnecessary under hot conditions. Stirring is maintained and optionalheating is maintained until the mixture is completely homogeneous.

Stage d: Preparation of the Fatty Phase (Optional):

The oily compounds (Olepal isostearique, Cetiol SN, Crodamol DA, SpeziolC18, Miglyol 812, Cosbiol type), the optional heat-insensitivelipophilic additives, if heating, and optionally the preservatives(phenoxyethanol, propylparaben type) are mixed in a beaker. The mixtureis heated until homogeneity is achieved and the volatile silicone, ifthe latter is present in the composition, is introduced.

Stage e: Mixing the Active Phases:

The two active phases respectively obtained in a) and b) are mixed at atemperature of less than 40° C. and stirring is maintained until themixture is completely homogeneous.

Stage f: Introduction of the Single Active Phase into the aqueous phase:

The single active phase obtained in stage e) is introduced into theaqueous phase obtained in stage c).

Stage g: (Optional) Addition of the Simulgel 600PHA:

The Simulgel 600PHA is introduced with stirring into the phase obtainedin f). Stirring is maintained until the Simulgel has completelydispersed.

Stage h: Addition of the Oil or of the Fatty Phase Obtained in d):

The single fatty phase constituent or optionally the fatty phaseobtained in stage d) is introduced into the mixture obtained in f) org).

Stage i (Optional): Addition of the Heat-Sensitive Additives:

The optional additives are introduced with stirring at a temperaturebelow 40° C. Stirring is maintained until the mixture is completelyhomogeneous.

Stage j (Optional): Neutralization:

The neutralization agent for the gelling agent (such as triethanolamine,the 10% sodium hydroxide solution, the citric acid/sodium citratebuffer, the succinic acid/sodium succinate buffer) or the pH buffer isintroduced, if necessary, at a temperature below 40° C. until at thedesired pH. The product then assumes a thicker consistency. Ifnecessary, the adjustment to 100% with water is carried out. The productis homogenized a final time to ensure the active principles, adapaleneand benzoyl peroxide, are satisfactorily dispersed (microscopicobservation revealing a homogeneous and aggregate-free dispersion) andthen the product is packaged.

Stage k: Correction of the Water Loss:

The water loss during the preparation of the product is calculated andthe lost water is re-added with stirring. Stirring is maintained untilthe mixture is completely homogeneous.

More specifically, by way of example, the alternative process for thepreparation of the composition according to the invention comprises thefollowing stages:

Stage a′: Preparation of the Single Active Phase:

Stages a) and b) of the main process are combined, so as to obtain stagea′), which corresponds to the mixing of at least one retinoid andbenzoyl peroxide with water and at least one wetting agent until theyhave completely dispersed, to obtain the single active phase.

Stages c), d), f), g), h), i), j) and k) of the main process remainunchanged. As regards stage e), this is deleted.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative. Insaid examples to follow, all parts and percentages are given by weight,unless otherwise indicated.

The formulation examples below illustrate the compositions according tothe invention without, however, limiting the scope thereof.

The term “physical stability of the formulations” means carrying outmacroscopic and microscopic observation at ambient temperature and 40°C., carried out at T1 month and T2 months.

Microscopic observation makes it possible to evaluate the quality of thedispersion of the two active principles. The adapalene is observed influorescent light while the benzoyl peroxide is observed in polarizedlight.

The characterization of the finished product is completed by ameasurement of the yield point and of viscosity.

For the measurement of the yield point, use is made of a Haake rheometerof VT550 type with an SVDIN measuring spindle.

The rheograms are produced at 25° C. and at the shear rate of 4 s⁻¹, 20s⁻¹ and 100 s⁻¹ (γ), the shear stress being measured. The term “yieldpoint” (τ0, expressed in pascals) means the force necessary (minimumshear stress) to overcome the cohesive forces of Van der Waals type andto bring about flow. The yield point is to be equated with the valuefound at the shear rate of 4 s⁻¹.

For the viscosity measurement, use is made of Brookfield RVDVII+ orLDVDII+ viscometers. The viscosity ranges which can be measured with thetwo Brookfield types are as follows:

RVDVII+: 100 cP-40 McP

LVDVII+: 15 cP-6 McP

The chemical stability is ensured by an HPLC quantitative determinationof the active principles.

The result is expressed in g/g of adapalene and of benzoyl peroxide andas % with respect to the expected content.

Example 1: Formulation of Cream Gel Type Comprising 0.1% Adapalene and2.5% Benzoyl Peroxide

The formulation is prepared according to the procedure described above.

Constituents Content (% w/w) Benzoyl peroxide 2.50 Adapalene 0.10Propylene glycol 5.00 Synperonic PE/L44 0.20 EDTA 0.10 Glycerol 5.00Xantural 180 0.10 Carbopol Ultrez 20 0.70 Marcol 152 7.00 Purified waterq.s. for 100% Sodium hydroxide, 10% w/w q.s. for pH 5.5 ± 0.5

Stability Data:

Physical Stability:

Characterizations at T0 Macroscopic appearance White cream gelMicroscopic appearance Dispersion of the active principles withoutaggregates of greater than 100 μm pH 5.144 Viscosity data Haake (4s⁻¹/20 s⁻¹/ 94/123/187 100 s⁻¹) Brookfield RVDVII+ (S28; 65 620 cP 5rpm) T + 1 month T + 2 months T + 3 months Macroscopic AT Identical toIdentical to T0 Identical to appearance T0 T0 40° C. Identical toIdentical to T0 Identical to T0 T0 Microscopic AT Identical to Identicalto T0 Identical to appearance T0 T0 40° C. Identical to Identical to T0Identical to T0 T0 pH AT 5.10 5.03 5.09 40° C. 4.96 4.74 4.59 Haakerheology 89/121/172 87/117/168 N.R. 4 s⁻¹/20 s⁻¹/100 s⁻¹ BrookfieldRVDVII+ 65 775 cP 63 820 cP 67 505 cP viscosity (S28; 5 rpm)

Chemical Stability:

Adapalene:

Time Stability conditions T0 T + 1 month T + 2 months AT g/g 0.10 0.100.10 % of the expected 100 100 100 content 40° C. g/g N.A. 0.10 0.11 %of the expected N.A. 100 110 content

Benzoyl Peroxide:

Time Stability conditions T0 T + 1 month T + 2 months AT g/g 2.7 2.7 2.7% of the expected 108 108 108 content 40° C. g/g N.A. 2.6 2.6 % of theexpected N.A. 104 104 content

Example 2: Formulation of Thick Cream Gel Type Comprising 0.1% Adapaleneand 2.5% Benzoyl Peroxide

The formulation is prepared according to the procedure described above.

Constituents Content (% w/w) Benzoyl peroxide 2.50 Adapalene 0.10Propylene glycol 6.00 Synperonic PE/L44 0.20 Glycerol 5.00ST-Cyclomethicone 5NF 7.00 Simulgel 600 PHA 4.00 Purified water q.s. for100%

Physical Stability:

Characterizations at T0 Macroscopic appearance White cream gelMicroscopic appearance Dispersion of the active principles withoutaggregates of greater than 100 μm pH 3.542 Viscosity data Haake (4s⁻¹/20 s⁻¹/ 236/296/449 100 s⁻¹) Brookfield RVDVII+ (S29; 164 650 cP 5rpm) T + 1 month T + 2 months T + 3 months Macroscopic AT Identical toIdentical to T0 Identical to appearance T0 T0 40° C. Identical toIdentical to T0 Identical to T0 T0 Microscopic AT Identical to Identicalto T0 Identical to appearance T0 T0 40° C. Identical to Identical to T0Identical to T0 T0 pH AT 3.47 3.36 3.50 40° C. 3.31 3.17 3.27 Haakerheology 223/286/389 201/268/334 N.R. 4 s⁻¹/20 s⁻¹/100 s⁻¹ BrookfieldRVDVII+ 159 070 cP 150 160 cP 132 720 cP viscosity (S29; 5 rpm)

Chemical Stability:

Adapalene:

Time T + 1 T + 2 Stability conditions T0 month months AT g/g 0.10 0.110.10 % of the expected content 100 110 100 40° C. g/g N.A. 0.10 0.10 %of the expected content N.A. 100 100

Benzoyl Peroxide:

Time T + 1 T + 2 Stability conditions T0 month months AT g/g 2.7 2.8 2.7% of the expected content 108 112 108 40° C. g/g N.A. 2.6 2.6 % of theexpected content N.A. 104 104

Example 3: Formulation of Fluid Cream Gel Type Comprising 0.3% Adapaleneand 1% Benzoyl Peroxide

The formulation is prepared according to the procedure described above.

Constituents Content (% w/w) Benzoyl peroxide 1.00 Adapalene 0.30Lauroglycol 2.00 Synperonic PE/L62 0.20 EDTA 0.10 Methylparaben 0.20Methocel E4M Premium 0.10 Carbopol ETD202NF 0.30 Olepal isostearique2.00 Cosbiol 8.00 Cetiol SN PH 8.00 Propylparaben 0.05 Sodium hydroxide,10% w/w q.s. for pH 5.5 ± 0.5 Purified water q.s. for 100%

Example 4: Formulation of Fluid Cream Gel Type Comprising 0.10%Adapalene and 0.25% Benzoyl Peroxide

The formulation is prepared according to the procedure described above.

Constituents Content (% w/w) Benzoyl peroxide 0.25 Adapalene 0.10Propylene glycol 2.00 Synperonic PE/L62 0.20 EDTA 0.10 Glycerol 5.00Methylparaben 0.20 Carbopol Ultrez-20 0.30 Veegum K 0.20 Xanthan gum0.20 ST-Cyclomethicone 5NF 7.00 Propylparaben 0.10 Triethanolamine q.s.for pH 5.5 ± 0.5 Purified water q.s. for 100%

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference in its entirety.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A method for the treatment of acne, comprisingtopically applying to the skin of an individual in need thereof, aneffective amount of a stable cream gel dermatological compositioncomprising, in a single formulation, (a) a homogeneous dispersion of afatty phase in an aqueous phase, comprising at least one dispersedretinoid and dispersed benzoyl peroxide as a single active phase; (b) atleast one lipophilic compound, other than the retinoid, selected fromthe group consisting of liquid paraffins, sweet almond oil, palm oil,soybean oil, sesame oil, sunflower oil, lanolin, squalene, fish oil,mink oil, squalane, cetearyl isononanoate, diisopropyl adipate,caprylic/capric triglyceride, a volatile or non-volatile silicone oiland natural or synthetic waxes; and (c) at least one gelling agent;formulated into a physiologically acceptable medium, wherein the fattyphase comprises the at least one lipophilic compound in an amount from5% to 30% by weight, relative to the total weight of the composition,and wherein the composition is devoid of any emulsifier.
 2. The methodof claim 1, wherein the composition comprises from 0.0001% to 20% byweight of the at least one retinoid, relative to the total weight of thecomposition.
 3. The method of claim 1, wherein the composition comprisesfrom 0.0001% to 20% by weight of benzoyl peroxide, relative to the totalweight of the composition.
 4. The method of claim 1, wherein the atleast one retinoid comprises adapalene.
 5. The method of claim 1,wherein the composition comprises from 0.001% to 15% by weight of the atleast one gelling agent, relative to the total weight of thecomposition.
 6. The method of claim 1, wherein the composition is solid.7. The method of claim 1, wherein the acne is comedonic acne,polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata,senile acne, solar acne, drug acne, or occupational acne.
 8. The methodof claim 1, wherein the acne is characterized by hyperseborrhea.